Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure
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{"title"=>"Oseltamivir resistance in influenza A(H6N2) caused by an R292K substitution in neuraminidase is not maintained in mallards without drug pressure", "type"=>"journal", "authors"=>[{"first_name"=>"Anna", "last_name"=>"Gillman", "scopus_author_id"=>"55821584800"}, {"first_name"=>"Shaman", "last_name"=>"Muradrasoli", "scopus_author_id"=>"16417267100"}, {"first_name"=>"Andreas", "last_name"=>"Mårdnäs", "scopus_author_id"=>"56971370000"}, {"first_name"=>"Hanna", "last_name"=>"Söderström", "scopus_author_id"=>"7004455432"}, {"first_name"=>"Ganna", "last_name"=>"Fedorova", "scopus_author_id"=>"56350574300"}, {"first_name"=>"Max", "last_name"=>"Löwenthal", "scopus_author_id"=>"56970959000"}, {"first_name"=>"Michelle", "last_name"=>"Wille", "scopus_author_id"=>"36572831000"}, {"first_name"=>"Annika", "last_name"=>"Daggfeldt", "scopus_author_id"=>"6508190979"}, {"first_name"=>"Josef D.", "last_name"=>"Järhult", "scopus_author_id"=>"26664701000"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84947796730", "pmid"=>"26422258", "pui"=>"606955581", "doi"=>"10.1371/journal.pone.0139415", "scopus"=>"2-s2.0-84947796730", "isbn"=>"1932-6203", "issn"=>"19326203"}, "id"=>"6f1dabed-b23e-3ddc-b07e-3e937eea53d1", "abstract"=>"BACKGROUND: Wild waterfowl is the natural reservoir of influenza A virus (IAV); hosted viruses are very variable and provide a source for genetic segments which can reassort with poultry or mammalian adapted IAVs to generate novel species crossing viruses. Additionally, wild waterfowl act as a reservoir for highly pathogenic IAVs. Exposure of wild birds to the antiviral drug oseltamivir may occur in the environment as its active metabolite can be released from sewage treatment plants to river water. Resistance to oseltamivir, or to other neuraminidase inhibitors (NAIs), in IAVs of wild waterfowl has not been extensively studied.\\n\\nAIM AND METHODS: In a previous in vivo Mallard experiment, an influenza A(H6N2) virus developed oseltamivir resistance by the R292K substitution in the neuraminidase (NA), when the birds were exposed to oseltamivir. In this study we tested if the resistance could be maintained in Mallards without drug exposure. Three variants of resistant H6N2/R292K virus were each propagated during 17 days in five successive pairs of naïve Mallards, while oseltamivir exposure was decreased and removed. Daily fecal samples were analyzed for viral presence, genotype and phenotype.\\n\\nRESULTS AND CONCLUSION: Within three days without drug exposure no resistant viruses could be detected by NA sequencing, which was confirmed by functional NAI sensitivity testing. We conclude that this resistant N2 virus could not compete in fitness with wild type subpopulations without oseltamivir drug pressure, and thus has no potential to circulate among wild birds. The results of this study contrast to previous observations of drug induced resistance in an avian H1N1 virus, which was maintained also without drug exposure in Mallards. Experimental observations on persistence of NAI resistance in avian IAVs resemble NAI resistance seen in human IAVs, in which resistant N2 subtypes do not circulate, while N1 subtypes with permissive mutations can circulate without drug pressure. We speculate that the phylogenetic group N1 NAs may easier compensate for NAI resistance than group N2 NAs, though further studies are needed to confirm such conclusions.", "link"=>"http://www.mendeley.com/research/oseltamivir-resistance-influenza-ah6n2-caused-r292k-substitution-neuraminidase-not-maintained-mallar", "reader_count"=>9, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>4, "Researcher"=>1, "Student > Ph. D. Student"=>1, "Student > Bachelor"=>2, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>4, "Researcher"=>1, "Student > Ph. D. Student"=>1, "Student > Bachelor"=>2, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>1, "Agricultural and Biological Sciences"=>2, "Chemistry"=>2, "Immunology and Microbiology"=>1, "Economics, Econometrics and Finance"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2294628"], "description"=>"<p>Primers for NA amplification and sequencing.</p>", "links"=>[], "tags"=>["iav", "sewage treatment plants", "H 1N virus", "N 1 subtypes", "H 6N virus", "Drug Pressure BackgroundWild waterfowl", "R 292K substitution", "oseltamivir drug pressure", "NAI resistance", "NAI sensitivity testing", "vivo Mallard experiment", "N 2 virus", "phylogenetic group N 1 NAs", "drug exposure", "N 2 subtypes", "group N 2 NAs"], "article_id"=>1560960, "categories"=>["Uncategorised"], "users"=>["Anna Gillman", "Shaman Muradrasoli", "Andreas Mårdnäs", "Hanna Söderström", "Ganna Fedorova", "Max Löwenthal", "Michelle Wille", "Annika Daggfeldt", "Josef D. Järhult"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139415.t001", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Primers_for_NA_amplification_and_sequencing_/1560960", "title"=>"Primers for NA amplification and sequencing.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-09-30 03:46:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2294629"], "description"=>"<p>The experiment was repeated three times with three H6N2/R292K resistant IAV variants, each consisting of five overlapping generations of Mallards, two birds in each.</p><p>*Oseltamivir carboxylate (OC) concentration in the experimental water with range of relative standard deviations (%RSD) for each of the three experiments at respective exposure level (n = 4 at 10 μg/L, n = 3 at 3 μg/L and n = 4 at 1 μg/L). The three experiments had the same OC concentration in the water. Dashed horizontal lines indicate change in OC concentrations.</p><p>G1 = generation one, G2 = generation two etc.</p><p>E1 = experiment with NA substitutions R292K + D113N. E2 = experiment with NA substitutions R292K + D141N. E3 = experiment with NA substitutions R292K. K displays lysine, R displays arginine, and <i>k</i> displays a mixed proportion of R and K at NA residue 292, as determined by Sanger sequencing of daily fecal samples of each bird. Wild type genotype correlated to unexposed Mallards (<i>P</i> = 0.000002)</p><p>Experimental design and NA sequence results of residue 292.</p>", "links"=>[], "tags"=>["iav", "sewage treatment plants", "H 1N virus", "N 1 subtypes", "H 6N virus", "Drug Pressure BackgroundWild waterfowl", "R 292K substitution", "oseltamivir drug pressure", "NAI resistance", "NAI sensitivity testing", "vivo Mallard experiment", "N 2 virus", "phylogenetic group N 1 NAs", "drug exposure", "N 2 subtypes", "group N 2 NAs"], "article_id"=>1560961, "categories"=>["Uncategorised"], "users"=>["Anna Gillman", "Shaman Muradrasoli", "Andreas Mårdnäs", "Hanna Söderström", "Ganna Fedorova", "Max Löwenthal", "Michelle Wille", "Annika Daggfeldt", "Josef D. Järhult"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139415.t002", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Experimental_design_and_NA_sequence_results_of_residue_292_/1560961", "title"=>"Experimental design and NA sequence results of residue 292.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-09-30 03:46:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2294630"], "description"=>"<p>Mean concentrations of drugs ± standard deviations that inhibited 50% (IC<sub>50</sub>) of the viral NA activity in a functional assay with the MUNANA substrate. 292R = arginine at NA residue 292. 292K = lysine at NA residue 292. Values were calculated on duplicates of six wild type (292R) and five mutated (292K) viral samples.</p><p>Viral NA inhibition by oseltamivir carboxylate and zanamivir.</p>", "links"=>[], "tags"=>["iav", "sewage treatment plants", "H 1N virus", "N 1 subtypes", "H 6N virus", "Drug Pressure BackgroundWild waterfowl", "R 292K substitution", "oseltamivir drug pressure", "NAI resistance", "NAI sensitivity testing", "vivo Mallard experiment", "N 2 virus", "phylogenetic group N 1 NAs", "drug exposure", "N 2 subtypes", "group N 2 NAs"], "article_id"=>1560962, "categories"=>["Uncategorised"], "users"=>["Anna Gillman", "Shaman Muradrasoli", "Andreas Mårdnäs", "Hanna Söderström", "Ganna Fedorova", "Max Löwenthal", "Michelle Wille", "Annika Daggfeldt", "Josef D. Järhult"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139415.t003", "stats"=>{"downloads"=>9, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Viral_NA_inhibition_by_oseltamivir_carboxylate_and_zanamivir_/1560962", "title"=>"Viral NA inhibition by oseltamivir carboxylate and zanamivir.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-09-30 03:46:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2294624"], "description"=>"<p>IAV was detected by RRT-PCR of the matrix gene from daily fecal samples. The Y-axis displays cycle threshold (CT) values as a quantitative measure of viral excretion. Samples with CT values ≥ 45 were considered negative. The X-axis displays which days of the experiment samples were collected from the Mallards. G1 = two birds in each of three experiments (n = 6), etc. G1 and G2 were OC exposed, G3 was OC exposed day 0–2, and G4 and G5 were unexposed. Value points display mean CT values of 6 samples and error bars display standard errors of the mean (SEM). No significant difference in excretion was detected between drug-exposed (G1 and G2 with resistant genotype NA-292K) and unexposed (G4 and G5 with wild type genotype NA-292R) birds day 1, 4 or 5, while drug-exposed birds had lower virus excretion levels day 2 and 3(<i>P</i> = 0.034).</p>", "links"=>[], "tags"=>["iav", "sewage treatment plants", "H 1N virus", "N 1 subtypes", "H 6N virus", "Drug Pressure BackgroundWild waterfowl", "R 292K substitution", "oseltamivir drug pressure", "NAI resistance", "NAI sensitivity testing", "vivo Mallard experiment", "N 2 virus", "phylogenetic group N 1 NAs", "drug exposure", "N 2 subtypes", "group N 2 NAs"], "article_id"=>1560958, "categories"=>["Uncategorised"], "users"=>["Anna Gillman", "Shaman Muradrasoli", "Andreas Mårdnäs", "Hanna Söderström", "Ganna Fedorova", "Max Löwenthal", "Michelle Wille", "Annika Daggfeldt", "Josef D. Järhult"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139415.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Viral_excretion_/1560958", "title"=>"Viral excretion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-30 03:46:14"}

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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